The development and application of the solution-phase synthesis of combinatorial libraries for screening in novel assays designed to identify new agents for the treatment of cancer are detailed. In the past efforts, over 40,000 compounds have been prepared and archived in existing libraries and this will be increased to 1,000,000 compounds under the present grant. Included in this library and as part of its expansion are templates and mimetics that target protein-protein or protein-DNA interactions. The screening of the current libraries and the subsequent lead optimization have provided (1) the first angiogenesis inhibitors exhibiting in vivo antitumor activity based on inhibition of MMP2 binding to integrin alphavbeta3, (2) the first small molecule inhibitors of Myc-Max dimerization that inhibit c-Myc-induced cell transformation, (3) the first inhibitors of intracellular Paxillin/alpha4 binding which serve to inhibit cell migration, (4) relatively small EPO agonists that act by promoting EPO receptor dimerization, and (5) two classes of inhibitors of LEF-1/beta-catenin mediated gene transcription. Continued efforts on these targets will complement new studies on additional targets.